Perspective:

A host of observational studies, registries, and post hoc analyses of randomized clinical trials done for other purposes have reported highly variable effects of cardiac glycosides on mortality, although the majority of them have suggested digoxin had a deleterious effect in heart failure and atrial fibrillation. The validity of those nonrandomized studies is premised on the assumption that adjustment for baseline covariates appropriately addresses hidden, unmeasured differences. The authors of the present study provide a cogent cautionary warning against accepting this presupposition.

The DIG trial, the large randomized trial of digoxin in heart failure, reported a neutral effect on mortality and a significant reduction in heart failure hospitalizations in patients randomized to digoxin. Almost one half of the patients enrolled in the study had been treated with digoxin prior to the study start and were randomized to either continue digoxin or receive a placebo treatment instead (randomized withdrawal).

The new observational analysis, nested in the DIG trial population, shows a significant increase in mortality and risk for heart failure hospitalization in patients who had taken digoxin prior to study randomization, even if treated with placebo in the trial. Both findings sharply contrast the results of the randomized comparison, which indicated that digoxin had a neutral effect on mortality but substantially decreased heart failure hospitalizations. The differences between patients pretreated and not pretreated with digoxin must have been so great that they could not be appropriately addressed with the statistical adjustment for baseline covariates.

This elegant manuscript has broader implications, which go well beyond the treatment of heart failure with digoxin, and it challenges the role of observational studies to reliably demonstrate efficacy of medical treatments in general.